Inflammation is reactions of blood membrane and cell against injury factor originated from injured cell and foreign material entered into body. 1) Metabolites of arachidonic acid, that is, prostaglandin, leukotriene, and lipoxins, 2) platelet activation factor, 3) cytokines like tumor necrosis factor-alpha, interleukin-1 (IL-1), etc. and chemokines like monocyte chemo-attractant protein (MCP-1), macrophage inflammatory protein-1alpha (MCP-1alpha), etc., 4) nitric oxide (NO), 5) reactive oxygen, 6) vasodilating factors such as histamine, serotonin, etc. are known to be materials intervening inflammation reaction. Main purpose of inflammation reaction is to remove extraneous material and injured cell (or cell tissue), but inflammation reaction can be a cause of chronic diseases like rheumarthritis and arteriosclerosis.
In case that the degree of inflammatory damage is small, limited and temporary, injury factors are removed and tissue comes back to normal state according to the termination of inflammation reaction. Inflammation reaction happening where there is large damage or regeneration ability is weak is accompanied with major tissue damage, which may cause dysfunction. Chronic inflammation reaction happening for a long time may be a cause of fatal tissue damage in rheumarthritis, arteriosclerosis, tuberculosis, chronic pulmonary disease, etc. (Pathological Basis of Disease, pp 47-86, 7th edition).
In addition, there are many literatures disclosing that inflammation plays a critical role in pathophysiology of degenerative brain disease. Microglia present in brain is activated at site where neuronal damage happens in Alzheimer's disease, Parkinson's disease and Lou Gehrig's disease (Liu B and Hong J S. J Pharmacol Exp Ther. 2003; 304(1):1-7; Orr C F et al., Prog Neurobiol. 2002; 68(5):325-40; and Henkel J S et al., Ann Neurol. 2004; 55(2):221-35). Activated microglia produces prostaglandins, cytokines, chemokines, reactive oxygen species, NO, etc., which begin inflammation reaction in brain (Minghetti L. Curr Opin Neurol. 2005; 18(3):315-21; Gao H M, Trends Pharmacol Sci. 2003; 24(8):395-401; Weydt P and Moller T. Neuroreport. 2005; 16(6):527-31; J. J. M. Hoozemans Int. J. Devl Neuroscience. 2006; 24:157-165). Therefore, administration of drug inhibiting inflammation is reported to suppress production of beta-amyloid and plague in animal model of Alzheimer's disease (Townsend K P and Pratico D. FASEB J. 2005; 18:315-21), protect dopaminergic neuronal cell in animal model of Parkinson's disease (Ferger B et al., Naunyn Schmiedebergs Arch Pharmacol. 1999; 360(3):256-61; Teismann P, Ferger B. Synapse. 2001; 39(2):167-74), prevent death of spinal motoneuron and reduce activity of glia in Lou Gehrig's disease model (Kiaei M et al., J. Neurochem. 2005; 93(2):403-11). Actually, an attack rate of Alzheimer's disease is high in patient having brain inflammation reaction caused by contusion, etc. (Breitner J C. Neurology. 1994; 44(2):227-32), and an attack rate of Alzheimer's disease is low in rheumarthritis patient taking nonsteroidal anti-inflammatory drugs (NSAIDs) for a long time (McGeer P L et al., Lancet. 1990; 335(8696):1037). In addition, it is reported that administration of NSAID not only prevents Alzheimer's disease, but also delays progress of damage of cognitive function (Rich et al., Neurology. 1995). These results suggest that a drug inhibiting inflammation reaction may be used for preventing and treating degenerative brain disease.
NSAIDs, drugs suppressing activity of cyclooxygenase taking part in production of prostaglandin, have been developed and widely used to alleviate symptoms, including pain, of inflammatory diseases, but there are side effects to block the use of the NSAIDs. Specifically, gastrointestinal disorders such as dyspepsia, gastritis, ulcer, bleeding and perforation are side effects often happening after administration of NSAIDs. Actually, because of adverse effects of NSAIDs, 107,000 of people are reported to be hospitalized and 16,500 of people are reported to be dead in USA only. Celecoxib and Rofecoxib, selective COX-2 (cyclooxygenase-2) enzyme inhibitors, having low side effects on gastrointestinal damage have been developed and used for treating arthritis and pain. However, U.S. FDA reported that long-term administration of celecoxib, rofecoxib and valdecoxib might cause heart disease, and prohibited the use of these as drug for treating arthritis. Furthermore, clinical trials to evaluate therapeutic efficacy of celecoxib and rofecoxib in dementia were discontinued because of their safety.
In addition, reactive oxygen species produced by neutrophil, macrophage, monocyte, etc. in inflammatory disease is known to be a major reason causing tissue damage by mediating inflammatory reaction. In actually, administration of drugs removing reactive oxygen are reported to be effective in treating gastric damage happing in inflammatory diseases (Matthews G M et al., Helicobacter. 2005; 10(4):298-306), pancreatic damage (Shi C et al., Pancreatology. 2005; 5(4-5):492-500), atherosclerosis (Tardif J C. Curr Atheroscler Rep. 2005; 7(1):71-7), colon damage (Oz H S et al., J Nutr Biochem. 2005; 16(5):297-304), joint damage (Henrotin Y E et al., Osteoarthritis Cartilage. 2003; 11(10):747-55), renal damage (Tian N et al., Hypertension. 2005; 45(5):934-9), river damage (Loguercio C et al., Free Radic Biol Med. 2003; 34(1):1-10) and cardiovascular damage (Haidara M A et al., Curr Vasc Pharmacol. 2006; 4(3):215-27). Furthermore, administration of NSAIDs causes production of reactive oxygen, and induces damage to the gastric mucous membrane. This gastric damage is reported to be lessened by administration of anti-oxidant material (Graziani G et al., Gut. 2005; 54(2):193-200).
Inflammation plays an important role in pathophysiology of digestive disease, respiratory disease or neuronal system disease, but the use of currently available drugs is limited because of the side effects of the drugs. Aspirin (acetylsalicylic acid), an anti-inflammatory drug, is known to suppress the action of NF-kB and c-Jun N-terminal kinase (Ko H W et al., J Neurochem. 1998; 71(4):1390-5), and sulfasalazine is known to protect cell by its anti-oxidant activity (Ryu B R et al., J Pharmacol Exp Ther. 2003; 305(1):48-56). However, there is a drawback that aspirin and sulfasalazine show their cell-protecting effects in high concentration only.